The identification of a large family of Fc receptor-like (FCRL) molecules expressed by terminally differentiated lymphocytes that possess tyrosine-based immunoregulatory properties has opened a new field of investigation. The fundamental immunologic importance of these molecules is indicated by their evolutionary conservation, emergence coincident with the birth of modern adaptive immunity, and associations with lymphoproliferative, infectious, immunodeficiency, and autoimmune disorders. Unfortunately, the interspecies diversity evident between human and mouse counterparts as well as the enigmatic nature of their ligands has limited our understanding of their biological roles. FCRL6, the focus of this proposal, has a discriminating expression pattern on mature human cytotoxic NK and T lymphocytes, is upregulated on these cells in chronic disease states, can recruit SHP-2, and has recently been found to interact with MHC class II. The discovery of this relationship exposes an unanticipated pathway in the regulation of cell-mediated immunity. Our central hypothesis is that the development of human FCRL6 BAC transgenic (Tg) mice will provide a critical translational tool for defining the potential of FCRL6 to regulate the effector function of cytotoxic lymphocytes through its interaction with MHC class II. The proposed research is innovative because it will develop a Tg model to overcome the hurdle of interspecies diversity evident for this receptor/gene in humans and mice and establish an in vivo system to explore the biology of the FCRL6/MHCII interface. Our preliminary studies strongly indicate that this approach will provide a significant breakthrough for determining the biological function of this molecule. We plan to test the central hypothesis by pursuing the following Specific Aims: Aim 1 proposes to characterize and further develop recently generated human FCRL6 BAC Tg mice and Aim 2 will use these mice to investigate FCRL6 regulation of effector lymphocyte responses to LCMV infection and the influence of its HLA class II ligand. The contribution of this research will be significant because it will provide a unique opportunity to surmount a major barrier in our understanding. This major advance will yield a widely adaptable system for defining the physiologic impact of the FCRL6/MHCII interaction on cytotoxic effector lymphocytes and immune function in general. Importantly, the exceptional set of resources and expertise assembled for conducting these studies is well positioned to take full advantage of the potential of this model in future immunologic investigation. The outcomes of this work are expected to have a positive impact because the resulting Tg mice will provide fundamental insight into the role of the FCRL6/MHCII relationship in cellular immunity. This new platform will be robust and highly flexible for expanding investigation of the FCRL6/MHCII axis in a broad number of immune-related disorders, infectious diseases, and malignancies. These studies will also facilitate the development of new targeted therapeutic interventions for modulating this interaction and effector lymphocyte function that are relevant to many human diseases. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will develop a novel system in mice to model the biological role of a human receptor and its interacting counterpart that regulate immune system cells critical for defense responses against viruses and malignant cells. The work will be important to NIH's mission because it will have broad impact that advances fundamental understanding of the immune system and has important implications for the development of new therapeutic approaches to patients with immune-related disorders.